Method and system for synthesizing nanocarrier based long acting drug delivery system for dexamethasone

ABSTRACT

The embodiments herein provide a nano-carrier system for delivering a long-acting injectable drug of dexamethasone and a method of synthesising the same. The dexamethasone entrapped nanoparticles are prepared using a lipid/phospholipid core which is coated by a polymer. The lipid and phospholipid are dissolved in organic solvent. This solution is transferred into an aqueous phase consisting of distilled water or a buffer. A solution of polymer is added drop wise. The drug entrapped nanoparticle formation is achieved by diffusion of the organic solvent within the aqueous solvent to obtain the nanoparticles. The drug gets entrapped within the nanoparticles via the anti-solvency effect of the aqueous matrix. The resulting drug nanocarriers are capable of releasing the drug in a slow rate upon injection. The synthesized drug carrying nanoparticles are cryopreserved stored for future administration. For better storage, the nanodispersion is dried to form a powder.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the priority of U.S. Provisional PatentApplication No. 61/856,745, filed on Jul. 21, 2013, with the title,“Long-Acting Injectable Dosage Form Based on Nanotechnology forDexamethasone”, and the content of which is incorporated herein byreference in its entirely.

BACKGROUND

1. Technical Field

The embodiments herein generally relate to the field of molecularnanotechnology. The embodiments herein particularly relate tonanomedicines or nanocarrier based drug delivery systems. Theembodiments herein more particularly relate to a system and method forsynthesizing long acting, and slow release nanoparticle or nano carrierbased drug delivery system for Dexamethasone.

2. Description of the Related Art

In nanotechnology, a particle is defined as a small object that becomesa whole unit with respect to its transport and properties. The particlesare further classified according to the diameter. The “nanoparticles”have a diameter within a range of 1 and 100 nanometer.

Nanotechnology has offered many advantages for novel drug deliverysystems in terms of both time-controlled drug delivery and site-directeddrug delivery. These advantages are mainly derived from the very small(submicron) sizes of the nanostructures used as nanocarriers for drugsas well as the possibility of engineering the carrier structure and/orsurface according to the particular biological requirements.

“Nanomedicine” is the medical application of nanotechnology.Nanomedicine ranges from the medical applications of nonmaterial's tonano-electronic biosensor and even possible future applications ofmolecular nanotechnology.

The current problems for nano-medicine involve understanding the issuesrelated to toxicity and the environmental impact on a nanoscalematerial.

The nano-medicine has provided the possibility of delivering drugs tospecific cells using nanoparticles. The overall drug consumption andside effects are lowered significantly by depositing an active agentonly in a morbid region at a required and appropriate dosage therebyeliminating a need for a higher dosage.

Drug delivery researchers are developing nanoscale particles ormolecules to improve a “bioavailability” of a drug. The termbioavailability refers to the presence of drug molecules where they areused in the body and where they act against an ailment. Drug deliverysystem mainly focuses on maximizing the bioavailability both at specificplaces in the body and over a period of time.

The drug delivery systems such as lipid or polymer based nanoparticlesare designed to improve the pharmacological and therapeutic propertiesof the drugs. Further, the metal based nanoparticles are also designedand developed to deliver the drugs.

The commonly used metals for nano-drug delivery system include but notlimited to gold, silver, platinum etc. The metal based nanoparticles forthe drug delivery system show toxicity. The recent studies in this arenahave shown that positively charged gold nanoparticles are found to enterkidney, while negatively charged gold nanoparticles remained in theliver and spleen. The positive surface charges of the nanoparticlesdecreases the rate of opsonization of nanoparticles in the liver,thereby affecting the excretory pathway. Even a relatively small size ofthe nanoparticles such as 5 nm can become compartmentalized in theperinephral tissues, and accumulate in the body over tissues. Theadvancement of research proves that targeting and distribution can beaugmented by nanoparticles and the dangers of nano-toxicity have becomean important question for the medical use in drug delivery.

A drug may cause tissue damage, but a drug delivery with regulated drugrelease can eliminate the problem. When a drug is removed too quicklyfrom the body, this rapid drug delivery could force a patient to use adose higher than a necessary dose. But a clearance can be reduced withdrug delivery systems by altering the pharmacokinetics of the drug. Apoor bio-distribution is a problem that can affect normal tissuesthrough a widespread drug distribution, but the particulates from thedrug delivery systems lower the volume of distribution and release theeffect on a non-target tissue. The potential nano-drugs works by veryspecific and well understood mechanisms, one of the major impacts ofnanotechnology and nano-science is the development of completely newdrug delivery systems with more useful behaviors and less side effects.

Long-acting injectable drug delivery systems can benefit from thepotentials of nanotechnology via the slow drug release from thenano-carriers already being loaded by the drug of interest. These drugcarriers may be administered by injection into the host body throughdifferent routes mainly including intravenous, intramuscular,subcutaneous, intra-dermal, intra-arterial, intra-thechal, andintra-cardiac administration. Basically, a drug dose loaded in anano-carrier is administered and the carrier, then supplies the drugneeded for the particular pharmacological effect for a more extendedtime following a single dose compared to a conventional bolus dose. Thepharmacokinetic outcome of the injectable long-acting dosage form isexpected to be the lack of fluctuations in plasma concentrations of thedrug which, eventually, results in avoiding the risks of over dosages,i.e., toxicity, or under dosages, i.e., treatment failure, in drugtherapy. When a particular drug is administered in a chronic (long-term)basis in the form of repeated doses, a fluctuation in drugconcentrations in plasma is observed. These pharmacokinetic fluctuationsdirectly result in pharmacodynamic fluctuations where the drug affectsthe site of action and experiences peaks and troughs at the same time ofconcentration changes or after a lag phase. These fluctuations in thedrug concentration are highly risky for patient, in particular for adrug like dexamethasone with narrow therapeutic index (small differencesbetween therapeutic and toxic doses). With the conventional, currentlyavailable products of the drug in the market, there is always a risk forthe patient to experience an overdosage (toxic effects in brain or othertissues) in the peak times or an underdosage (insufficient drug effect),both the stages are harmful for the patient.

Dexamethasone is a potent synthetic member of the glucocorticoid classof steroid drugs that has both the anti-inflammatory andimmune-suppressant effects. Dexamethasone is twenty five times morepotent than cortisol in its glucocorticoid effect while having minimalmineral corticoid effect. Dexamethasone is used to treat manyinflammatory and autoimmune conditions, such as rheumatoid arthritis andbronchospasms, dental surgery in nasal drops, cancer patients undergoingchemotherapy are given dexamethasone to counteract certain side effectsof their anti-tumor treatment dexamethasone.

The dexamethasone is one of the most effective and most widely usedanti-inflammatory and immune-suppressant drugs. The formulation of along-acting product from dexamethasone has the potential to improve thepatient outcome as well as the patient comfort, thereby improving theoverall success of chronic therapy with this drug which obviously isresulted from the achievement of a long time concentration of the drugin the range of vicinity of the site of action. The lipid based as wellas polymeric-based nanoparticles are prepared and loaded with the drugdexamethasone, which, upon entry to the host body via injection, servesas a drug reservoir capable of releasing the drug for long time periodsin blood circulation. This long-term drug profile is used as a basis fora prolonged chronic drug action toward the desired effects.

The dexamethasone is one of the most effective and most widely usednarcotic analgesics. The analgesic drugs with well known indications inthe relief of moderate to severe pains as well as the treatment of opoiddependence. The formulation of a long-acting product from dexamethasonehas a potential to improve the patient outcome as well as the patientcomfort so that the overall success of chronic therapy with this drug isresulted obviously from the achievement of a long time activity of thedrug in vicinity of the site of action with a reasonable concentration.The lipid based as well as polymeric-based nanoparticles are preparedand loaded by the drug dexamethasone which serves as a drug reservoircapable of releasing the drug for long time periods in bloodcirculation, upon entry to the host body via injection. This long-termdrug profile is used as a basis for prolonged chronic drug action towardthe desired effects.

Hence there is a need to develop a nanoparticle based drug deliverysystem for dexamethasone without any threat of cytotoxicity. Also thereis a need for a nanoparticle drug delivery system for dexamethasone torelease the drug slowly and in a controlled manner to an action site.Further there is a need to develop a method for synthesizing the organicbiomolecule based nanoparticle drug delivery system for dexamethasone.

The above mentioned shortcomings, disadvantages and problems areaddressed herein and which will be understood by reading and studyingthe following specification.

OBJECTIVES OF THE EMBODIMENTS

The primary objective of the embodiments herein is to synthesize a nanocarrier based long acting drug delivery system for dexamethasone using alipid core coated with a polymer.

Another objective of the embodiments herein is to synthesize the drugcarrying nanoparticles or nanocarrier entrapping dexamethasone withinthe nanoparticles.

Yet another objective of the embodiments herein is to synthesize thedrug nanocarrier based long acting drug delivery system fordexamethasone to provide a controlled release of the drug at a slow rateupon administration to an individual.

Yet another objective of the embodiments herein is to synthesize thedrug nanocarrier based long acting drug delivery system fordexamethasone to enable an administration of a drug through intravenous,intramuscular, subcutaneous, intra-dermal, intra-arterial, intra-thecaland intra-cardiac routes.

Yet another objective of the embodiments herein is to synthesize thedrug nanocarrier based long acting drug delivery system fordexamethasone by entrapping the drug using the anti-solvency effect ofthe aqueous matrix.

Yet another objective of the embodiment herein is to synthesize the drugnanocarrier based long acting drug delivery system for dexamethasone tocryoprotect the drug nanocarrier for future use and application.

These and other objects and advantages of the embodiments herein willbecome readily apparent from the following detailed description taken inconjunction with the accompanying drawings.

SUMMARY

The various embodiments herein provide a system and method for thesynthesis of the nanocarrier based drug delivery system fordexamethasone. The drug carrying nanoparticles or nanocarriers areprepared using a lipid/phospholipid core coated with a polymer. Thenanocarriers entrap the dexamethasone drug for site directed drugdelivery and slow release.

According to one embodiment herein, a method is provided forsynthesizing slow and controlled release of a dexamethasone entrapped innanoparticle or nanocarrier. The method comprises the steps ofdissolving a dexamethasone in an organic solvent to get an organicsolution. The dexamethasone is dissolved at a concentration of 0.1 to 10mg/ml in the organic solvent. The organic solvent is 0.1 to 5 mg/ml. Aphospholipid is added to the organic solution to form a bilayer aroundthe dexamethasone. A lipid is added to the organic solution to obtain anorganic solution mixture, and the organic solution mixture comprisesorganic solvent dissolved with the dexamethasone, phospholipid andlipid. The organic solution mixture is added in dropwise to an aqueoussolution to form a lipid core and the pH of the aqueous solution is in arange of 3-11. The volume ratio of the organic solution mixture to theaqueous solution is within 0.05 to 3. A buffered solution of a polymeris added to the aqueous solution with lipid core to form a coating layeraround the lipid core to obtain a nano carrier. The pH of the polymersolution is in a range of 3.5 to 11. The polymer solution is added indropwise/drops to the aqueous solution in a volume ratio of 0.05 to 1.

The organic solvent is selected from a group consisting of a methanol,an ethanol, an acetone and an isopropanol. The phospholipid is selectedfrom a group consisting of a phosphatidylcholine, aphosphatidylethanolamine, a phosphatidylinositol. The lipid is selectedfrom a group consisting of a monostearyl glycerol, a distearyl glycerol,a palmitic acid, a stearic acid and a glyceryl stearate. The polymer isselected from a group consisting of a chitosan, a polyethylene glycol, apolyvinyl alcohol.

According to one embodiment herein, a system is provided for a slow andcontrolled release of a dexamethasone entrapped in nanoparticle ornanocarrier. The system comprises a core of aqueous phase or solution, alipid layer, a phospholipid bilayer with the dexamethasone and a polymercoating. The aqueous solution is made of water or a buffer. Thephospholipid is selected from a group consisting of aphosphatidylcholine, a phosphatidylethanolamine, a phosphatidylinositol.The lipid is selected from a group consisting of a monostearyl glycerol,a distearyl glycerol, a palmitic acid, a stearic acid and a glycerylstearate. The polymer is selected from a group consisting of a chitosan,a polyethylene glycol, a polyvinyl alcohol.

The dexamethasone is water-insoluble and is present in a phospholipidbilayer during a formation of a nanovesicle. The dexamethasone getsloaded to the nanocarriers in a dissolved condition within a thicknessof the bilayers. The dexamethasone nanocarrier or nanoparticle particlesize distribution curve exhibits a peak of 128.5 nm and wherein thedexamethasone nanocarrier has a relative low polydisparity index of0.180. The dexamethasone nanocarrier or nanoparticle has a zetapotential within a range of 10 mv to 30 mv. The dexamethasonenanocarrier or nanoparticle has a zeta deviation of 4.71 mv. Thedexamethasone nanocarriers or nanoparticles are administeredintravenously, intramuscularly, sub-cutaneously, intra-dermally,intra-arterially, intra-thecaly and intra-cardiac routes.

These and other aspects of the embodiments herein will be betterappreciated and understood when considered in conjunction with thefollowing description and the accompanying drawings. It should beunderstood, however, that the following descriptions, while indicatingpreferred embodiments and numerous specific details thereof, are givenby way of illustration and not of limitation. Many changes andmodifications may be made within the scope of the embodiments hereinwithout departing from the spirit thereof, and the embodiments hereininclude all such modifications.

BRIEF DESCRIPTION OF THE DRAWINGS

The other objects, features and advantages will occur to those skilledin the art from the following description of the preferred embodimentand the accompanying drawings in which:

FIG. 1 illustrates a schematic representation of the processes for thepreparation of organic phase, aqueous phase and polymer phase solutionsin the method for synthesizing a nano carrier based long acting drugdelivery system for dexamethasone, according to an embodiment herein.

FIG. 2 illustrates a schematic representation of a method forsynthesizing a nano carrier based long acting drug delivery system fordexamethasone, according to an embodiment herein.

FIG. 3 illustrates a flowchart indicating a method for synthesizing anano carrier based long acting drug delivery system for dexamethasone,according to an embodiment herein.

FIG. 4 illustrates a graph indicating a size distribution profile of thedrug nano-carriers for dexamethasone, according to an embodiment herein.

FIG. 5 illustrates a graph indicating the zeta potential distributionprofile of the drug nano-carriers/nanoparticles for dexamethasone,according to one embodiment herein.

FIG. 6 illustrates a graph indicating the drug release profile ofdexamethasone from a nano carrier based long acting drug delivery systemfor dexamethasone, according to one embodiment herein.

FIG. 7 illustrates a schematic structure of a nano carrier based longacting drug delivery system for dexamethasone, according to oneembodiment herein.

Although the specific features of the embodiments herein are shown insome drawings and not in others. This is done for convenience only aseach feature may be combined with any or all of the other features inaccordance with the embodiments herein.

DETAILED DESCRIPTION OF THE EMBODIMENTS

In the following detailed description, a reference is made to theaccompanying drawings that form a part hereof, and in which the specificembodiments that may be practiced is shown by way of illustration. Theembodiments are described in sufficient detail to enable those skilledin the art to practice the embodiments and it is to be understood thatthe logical, mechanical and other changes may be made without departingfrom the scope of the embodiments. The following detailed description istherefore not to be taken in a limiting sense.

The various embodiments herein provide a system and method for thesynthesis of the nanocarrier based drug delivery system fordexamethasone. The drug carrying nanoparticles or nanocarriers areprepared using a lipid/phospholipid core coated with a polymer. Thenanocarriers entrap the dexamethasone drug for site directed drugdelivery and slow release.

According to one embodiment herein, a method is provided forsynthesizing slow and controlled release of a dexamethasone entrapped innanoparticle or nanocarrier. The method comprises the steps ofdissolving a dexamethasone in an organic solvent to get an organicsolution. The dexamethasone is dissolved at a concentration of 0.1 to 10mg/ml in the organic solvent. The organic solvent is 0.1 to 5 mg/ml. Aphospholipid is added to the organic solution to form a bilayer aroundthe dexamethasone. A lipid is added to the organic solution to obtain anorganic solution mixture, and the organic solution mixture comprisesorganic solvent dissolved with the dexamethasone, phospholipid andlipid. The organic solution mixture is added in dropwise to an aqueoussolution to form a lipid core and the pH of the aqueous solution is in arange of 3-11. The volume ratio of the organic solution mixture to theaqueous solution is within 0.05 to 3. A buffered solution of a polymeris added to the aqueous solution with lipid core to form a coating layeraround the lipid core to obtain a nano carrier. The pH of the polymersolution is in a range of 3.5 to 11. The polymer solution is added indropwise/drops to the aqueous solution in a volume ratio of 0.05 to 1.

The organic solvent is selected from a group consisting of a methanol,an ethanol, an acetone and an isopropanol. The phospholipid is selectedfrom a group consisting of a phosphatidylcholine, aphosphatidylethanolamine, a phosphatidylinositol. The lipid is selectedfrom a group consisting of a monostearyl glycerol, a distearyl glycerol,a palmitic acid, a stearic acid and a glyceryl stearate. The polymer isselected from a group consisting of a chitosan, a polyethylene glycol, apolyvinyl alcohol.

According to one embodiment herein, a system is provided for a slow andcontrolled release of a dexamethasone entrapped in nanoparticle ornanocarrier. The system comprises a core of aqueous phase or solution, alipid layer, a phospholipid bilayer with the dexamethasone and a polymercoating. The aqueous solution is made of water or a buffer. Thephospholipid is selected from a group consisting of aphosphatidylcholine, a phosphatidylethanolamine, a phosphatidylinositol.The lipid is selected from a group consisting of a monostearyl glycerol,a distearyl glycerol, a palmitic acid, a stearic acid and a glycerylstearate. The polymer is selected from a group consisting of a chitosan,a polyethylene glycol, a polyvinyl alcohol.

The dexamethasone is water-insoluble and is present in a phospholipidbilayer during a formation of a nanovesicle. The dexamethasone getsloaded to the nanocarriers in a dissolved condition within a thicknessof the bilayers. The dexamethasone nanocarrier or nanoparticle particlesize distribution curve exhibits a peak of 128.5 nm and wherein thedexamethasone nanocarrier has a relative low polydisparity index of0.180. The dexamethasone nanocarrier or nanoparticle has a zetapotential within a range of 10 mv to 30 mv. The dexamethasonenanocarrier or nanoparticle has a zeta deviation of 4.71 mv. Thedexamethasone nanocarriers or nanoparticles are administeredintravenously, intramuscularly, sub-cutaneously, intra-dermally,intra-arterially, intra-thecaly and intra-cardiac routes.

According to an embodiment herein, the drug carrying nanoparticles areprepared using a lipid/phospholipid core which is then, coated by apolymer. The lipid part, stearic acid, lipoic acid, monostearin,distearin, and cholesterol are used in conjugation with phospholipidpart which acts as the stabilizer for the solid lipid. As thephoospholipid part, phosphatidyl choline (lecithin) and/or phosphatidylethanolamaine are used. The chitosan, alginate, poly (vinyl alcohol),poly (ethylene glycol), poly (vinyl pyrrolidone) are the polymers usedin this process for coating.

According to one embodiment herein, dexamethasone is a potent syntheticmember of the glucocorticoid class of steroid drugs that has both theanti-inflammatory and immune-suppressant effects. Dexamethasone is oneof the most effective and most widely used corticosteroid drugs.Dexamethasone is well known for the positive indications and therapeuticprofiles in the clinical conditions requiring an anti-inflammatory drug.Dexamethasone is mainly used in the diseased states of asthma,arthritis, meningitis, auto-immune diseases etc. Dexamethasone is twentyfive times more potent than cortisol in its glucocorticoid effect whilehaving minimal mineral corticoid effect. Dexamethasone is used to treatmany inflammatory and autoimmune conditions, such as rheumatoidarthritis and bronchospasms. Dexamethasone is used in dental surgery asnasal drops. The cancer patients undergoing chemotherapy are givendexamethasone to counteract certain side effects of their anti-tumortreatment dexamethasone. The structure of dexamethasone is shown asbelow:

According to one embodiment herein, the first step in the process ofsynthesizing the dexamethasone drug based nanocarriers is dissolving thelipid and phospholipid in an organic solvent. The organic solvent ischosen from a group comprising acetone, ethanol, and methanol. Theconcentration of the organic solvent is in the range of 0.1 to 5 mg/ml.The solution of lipid and phospholipid in an organic solvent istransferred into an aqueous phase consisting of distilled water or abuffer with pH of 3-11. The drug (dexamethasone) to be entrapped in thenanoparticles/nanocarriers is present in the aqueous phase at aconcentration of 0.1 to 10 mg/ml. The volume ratio of organic-to-aqueousphase mixture is within a range of 0.05-3. The mixture obtained is mixedwith a solution of the polymer. The polymer solution is prepared in abuffered medium with a pH range of 3.5 to 11.0. The polymer solution isadded in drops or drop-wise to the organic-to-aqueous phase mixture in avolume ratio of 0.05 to 1.

According to an embodiment herein, the nanocarriers are capable ofreleasing the dexamethasone drug in a slow rate upon injection viaintravenous, intramuscular, subcutaneous, intradermal, intrathecal andintracardiac routes.

According to one embodiment herein, the particle formation is achievedmechanistically by the diffusion (dilution) of the organic solventwithin the aqueous host solvent to obtain the particles. The interesteddrug is entrapped in the nanoparticles/nanocarrier via the antisolvencyeffect of the aqueous matrix. The basis for the preparation of thephospholipid-based nanocarriers is a method known as “ethanol injection”with some modifications. In this method, the phospholipid, which ispractically insoluble in water, is dissolved in a water-misciblesolvent, typically ethanol. The ethanol is gradually added drop-wise toa higher amount of water (for example 10-times the ethanolic solutionvolume). When the phospholipid conies into contact with ethanol in thewater phase, ethanol “diffuses” into the water phase and becomes dilutedleading to a formation of new solvent which is mainly water with a smallportion of the ethanol. Since the phospholipid cannot be dissolved inthis new solvent and there is a vigorous shaking in system on the otherhand, the amphiphillic phospholipids undergoes a self-assembling processby using the vesicles made of phospholipid bilayers as the shells and anentrapped water phase as the core, and the core is surrounded by thephospholipid bilayers. When a drug such as “dexamethasone”, which isinsoluble in water, presents itself in the medium at the time ofnanovesicle formation, dexamethasone becomes loaded to the nanocarriersin a dissolved condition within the thickness of bilayers, as the onlypossibility for the dexamethasone to stay in this medium in athermodynamic point of view, during the formation of the self assembliesbecause the drug is hydrophobic and cannot be found in any proportionwithin the core of the surrounding waters.

According to one embodiment herein, the nanocarrier has alipid-phospholipid-polymer structure each of the components offer adefinite property to the drug delivery system. The lipid fraction makesthe system a suitable carrier for lipiphilic drugs such asdexamethasone. The lipid fraction restricts the rapid release of thedrug from the nanocarrier. The phospholipid component makes the systemmore amphiphillic to incorporate the lipophillic, the hydrophilic andthe amphiphillic drugs. The presence of this phospholipid fractionoffers the self assembly behaviour to the nanocarrier. The polymerforming a coating on the outer shell of the nanocarrier provides asurface charge, fluidity and mechanical strength.

According to one embodiment herein, the materials used for the synthesisof the drug nanocarriers/nanoparticles are divided into four groups. Thefour groups are organic solvents, phospholipids, lipids and polymers.The organic solvents which are used for the synthesis of the drugnanocarrier/nanoparticle are methanol, ethanol, acetone and isopropanol.The phospholipids which are used for the synthesis of the drugnanocarrier/nanoparticle are phosphatidylcholine,phosphatidylethanolamine and phosphatidylinositol. The lipids which areused for the synthesis of the drug nanocarrier/nanoparticle aremonostearyl glycerol, distearyl glycerol, palmitic acid and stearicacid. The polymers which are used for the synthesis of the drugnanocarrier/nanoparticle are chitosan, polyethylene glycol, ad polyvinylalcohol. The aqueous solution is a water or a buffer, which is used forthe formation of the core.

According to one embodiment herein the drug such as dexamethasone indifferent concentrations is taken for the preparation of the drugcarrying nanoparticles/nanocarriers based on specific objectives,therapeutic dosages and indications. The drug such as dexamethasone isthen dissolved in organic solvent such as ethanol, methanol, or acetoneto get a solution. The lipid (mainly a glyceryl stearate) is added indifferent amounts (quantities) to the solution of dexamethasone andorganic solvent. The lipid is added in a specific concentrationdepending on the drug and organic solvent concentrations. This solutionmixture consisting of drug (dexamethasone), organic solvent and lipid isadded drop wise into an aqueous phase (water or buffer) to form thelipid cores. The buffered aqueous solution of the polymer with differentconcentrations is added dropwise onto the cores based on the amounts orquantities of other compounds present in the solution to form thecoatings or shells around the phospholipid core.

According to one embodiment herein, the nanoparticle/nanocarriers aresubjected to in-vitro characterization tests, after the synthesis ofdexamethasone drug entrapped nanoparticle/nanocarriers.

According to one embodiment herein, the particle size distribution ofthe nano-dispersion is evaluated using the Dynamic Light Scattering(DLS) method. The surface zeta potential of the nano-dispersion is alsoevaluated by the electrophoretic mobility method. The drug releaseprofile of the nanoparticles is most important factor and is analyzed invitro.

According to one embodiment herein, the synthesized drug loadednanoparticle/nanocarrier is dried to form a powder using afreezer-dryer. The freeze-drying process enables the better storage.Glucose, lactose, trehalose, sorbitol, glycerol, mannitol or Tween areused in a concentration of 0.25-5%, for cryopreservation, Thecharacterization reveals an aqueous core with drug surrounded by aphospholipid bilayer. The lipid core is surrounded by the polymer shell.Two kinds of substances such as cryoprotectant and lyoprotectant areused for the cryopreservation by freeze-drying method of the drug loadednanocarriers or nanoparticles. The role of cryoprotectant is to preventirreversible aggregation of the nanoparticles during the freezingprocess. The cryoprotectant and lyoprotectant materials are mixed withthe nanoparticles/nanocarriers (nano-dispersion) before drying. When thefreezing process is carried out on the samples, the cryoprotectant andlyoprotectant materials provide either a physical barrier or anelectrical barrier around each nanocarrier or align the particles insolid-liquid interfaces during the freezing process resulting in theprotection of each individual carrier from being aggregated with theneighbouring particles. The lyoprotectants also play a similar role. Thecommonly used cryoprotectants and lyoprotectants are monosaccharides,disaccharides, polyols and non-ionic surfactants.

According to one embodiment herein, there are four mechanismsresponsible for the drug release from a nanocarrier when administered toan individual. The mechanisms are passive diffusion, based on theFickian kinetics, nanocarrier erosion occurring with time resulting indrug release, water penetration inside nanoparticles followed bychanneling (the drug is dissolved and diffused based on the drugconcentration gradient) and nanocarrier capture by the natural defencecells of the host body, then drug release out of the vehicle. Thesemechanisms contribute to the drug release from the nanocarrier.

FIG. 1 illustrates a schematic representation of the processes for thepreparation of organic phase, aqueous phase and polymer phase solutionsin the method for synthesizing a nano carrier based long acting drugdelivery system for dexamethasone, according to an embodiment herein. Alipid and a phospholipid are dissolved in an organic solvent in abeaker. The organic solvent are selected from an acetone or an ethanolor a methanol (101). The lipid and phospholipid are dissolved in theorganic solvent by a magnetic stirrer 104. The drug such asdexamethasone is then dissolved in organic solvent such as ethanol,methanol, or acetone to get a solution (101). The lipid (mainly aglyceryl stearate) is added in different amounts (quantities) to thesolution of dexamethasone and organic solvent. The lipid is added in aspecific concentration depending on the drug and organic solventconcentrations. This solution mixture consisting of drug(dexamethasone), organic solvent and lipid is added drop wise into anaqueous phase (water or buffer) to form the lipid cores (102). Thebuffered aqueous solution of the polymer with different concentrationsis added dropwise onto the cores based on the amounts or quantities ofother compounds present in the solution to form the coatings or shellsaround the phospholipid core. Finally, a buffered aqueous solution ofthe polymer such as a poly cation with a pH of 3.5 to 11 and aconcentrations based on the amount of other compounds is added dropwiseonto the lipid cores to form the coats around the lipid cores (103) andthe drug entrapped nanocarrier is obtained. The polymer solution isadded dropwise to the organic to aqueous phase in a volume ratio of 0.05to 1. The dexamethasone is water insoluble and presents itself in thephospholipid bilayer. In a beaker a lipid and a phospholipid aredissolved in an organic solvent. The organic solvent are selected froman acetone or an ethanol or a methanol. The lipid and phospholipid aredissolved in the organic solvent by a magnetic stirrer.

FIG. 2 illustrates a schematic representation of a method forsynthesizing a nano carrier based long acting drug delivery system fordexamethasone, according to an embodiment herein. The dexamethasone indifferent salts concentrations is taken Based on the specificobjectives, therapeutic dosages and indications. The dexamethasone isdissolved in an organic solvent, ethanol, methanol or acetone (201). Theorganic solvent has a concentration of 0.1 to 5 mg/ml. The dexamethasoneto be entrapped is taken in the concentration of 0.1 to 10 mg/ml. Thendifferent amounts of the phospholipid, mainly phosphatidylcholine, aredissolved in this solution and, finally, the lipid, mainly a glycerylstearate, is dissolved in the same solution with a preset concentrationdepending on the drug and the organic solvent components (202). Themixing of organic solvent with dexamethasone, lipid and phospholipidyields a solution mixture-A (203). The solution-A is added dropwise ontoan aqueous phase such as water or buffer with a pH in the range of 3-11(204). The lipid cores-C are formed aqueous phase (205). The volumeratio of the organic to the aqueous phase mixtures is 0.05 to 3.Finally, a buffered aqueous solution of the polymer such as a polycation with a pH of 3.5 to 11 with different concentrations, based onthe amount of other compounds, is added dropwise onto the lipid cores toform the coats around the lipid cores (206) and the drug nanocarriers Dare obtained (207). The polymer solution is added dropwise to theorganic to aqueous phase in a volume ratio of 0.05 to 1. Thedexamethasone is water insoluble and presents itself in the phospholipidbilayer.

FIG. 3 illustrates a flowchart indicating a method for synthesizing anano carrier based long acting drug delivery system for dexamethasone,according to an embodiment herein. The dexamethasone at different saltsin different concentrations is taken Based on the specific objectives,Therapeutic dosages and indications. The dexamethasone is dissolved inan organic solvent, ethanol, methanol or acetone (301). The organicsolvent has a concentration of 0.1 to 5 mg/ml. The dexamethasone to beentrapped is taken in the concentration of 0.1 to 10 mg/ml. Thendifferent amounts of the phospholipid, mainly phosphatidylcholine, aredissolved in this solution and, finally, the lipid, mainly a glycerylstearate, is dissolved in the same solution with a preset concentrationdepending on the drug and the organic solvent components (302). Themixing of organic solvent with dexamethasone, lipid and phospholipidyields a solution mixture-A (303). The solution-A is added dropwise ontoan aqueous phase such as water or buffer with a pH in the range of 3-11(304). The lipid cores-C are formed aqueous phase (305). The volumeratio of the organic to the aqueous phase mixtures is 0.05 to 3.Finally, a buffered aqueous solution of the polymer such as a polycation with a pH of 3.5 to 11 with different concentrations, based onthe amount of other compounds, is added dropwise onto the lipid cores toform the coats around the lipid cores (306). The polymer solution isadded dropwise to the organic to aqueous phase in a volume ratio of 0.05to 1. The drug nanocarriers D are obtained (307). The dexamethasone iswater insoluble and presents itself in the phospholipid bilayer.

Example 1 Synthesis Of Dexamethasone Carrying Nanoparticle/Nanocarrier

The following materials are required for the synthesis of nano carrierbased drug delivery system for dexamethasone.

-   -   1. Organic solvent: methanol, ethanol, acetone, isopropanol;    -   2. Phospholipids: Phosphatidylcholine, phosphatidylethanolamine,        phosphatidylinositol;    -   3. Lipids: Monostearyl glycerol, Distearyl glycerol, Palmitic        acid, Stearic acid    -   4. Polymers: chitosan, polyethylene glycol, polyvinyl alcohol.

Prodedure:

In the first step based on the specific objectives, therapeutic dosagesand indications the dexamethasone at different salts in differentconcentrations is taken. The dexamethasone is dissolved in an organicsolvent, ethanol, methanol or acetone. The organic solvent has aconcentration of 0.1 to 5 mg/ml. The dexamethasone to be entrapped istaken in the concentration of 0.1 to 10 mg/ml. Then different amounts ofthe phospholipid, mainly phosphatidylcholine, are dissolved in thissolution and, finally, the lipid, mainly a glyceryl stearate, isdissolved in the same solution with a preset concentration depending onthe drug and the organic solvent components. The mixing of organicsolvent with dexamethasone, lipid and phospholipid yields a solutionmixture-A. The solution-A is added dropwise onto an aqueous phase suchas water or buffer with a pH in the range of 3-11. The lipid cores-C areformed aqueous phase. The volume ratio of the organic to the aqueousphase mixtures is 0.05 to 3. Finally, a buffered aqueous solution of thepolymer such as a poly cation with a pH of 3.5 to 11 with differentconcentrations, based on the amount of other compounds, is addeddropwise onto the lipid cores to form the coats around the lipid coresand the drug nanocarriers D are obtained. The polymer solution is addeddropwise to the organic to aqueous phase in a volume ratio of 0.05 to 1.The dexamethasone is water insoluble and presents itself in thephospholipid bilayer.

FIG. 4 illustrates a graph indicating a size distribution profile of thedrug nano-carriers for dexamethasone, according to an embodiment herein.With respect to FIG. 4, the particle size distribution of thenanoparticles is analyzed by DLS analysis. The curves in the graph ofFIG. 4 are the long-normal probability curves. In the graph, log of thediameters of the nanoparticle populations is plotted against therelative contribution of the probability in the total number ofparticles based on the scattered light intensity from eachsub-population. The particle size distribution curves in FIG. 4 exhibitonly one peak (128.5 nm) with a relatively low polydispersity index(0.180). This indicates an ideal size of the nanoparticles with only onepeak representing a unimodal size distribution.

FIG. 5 illustrates a graph indicating the zeta potential distributionprofile of the drug nano-carriers/nanoparticles for dexamethasone,according to one embodiment herein. The zeta potential characterizes theelectrical potential on the surface of a colloid. This parameter is of aparticular importance both regarding the in vitro stability of thenanoparticles owing to the presence of a minimum electrical repulsionbetween the particles and also the in vivo fate of the nanocarrier uponentry to the host organism. The fate of the nanoparticles is regardingthe effect of the surface potential on the capture of the nanoparticlesby the natural defence mechanisms of the organism. The zeta potentialrequired for the stability of the nanoparticles is 10 mv-30 mv. FIG. 5shows the in vitro stability a potential of nanoparticles to be around30 mv is ideal but not less than 10 mv. Also for the fate of thenanoparticles, a zeta potential between +30 mv and −30 mv is ideal, butthe positive potential is the mostly preferred than neutral thannegative, which is shown by the nanoparticles in FIG. 5. The FIG. 5further illustrates the narrow distribution of the zeta potentials ofthe nanoparticles with a zeta deviation of 4.71 mv, is a very promisingresult along with the unimodal distribution (only one peak) of the zetapotentials which is again promising with respect to the homogeneity ofthe particles.

FIG. 6 illustrates a graph indicating the drug release profile ofdexamethasone from a nano carrier based long acting drug delivery systemfor dexamethasone, according to one embodiment herein. In FIG. 6, thegradual release of the drug with a near-constant (a straight line)release rate is observed as an ideal behaviour of a controlled releasesystem. FIG. 6 further illustrates the absence of a significant burst ofdrug release in initial stages. Also the considerable high plateau timeof 36 hours is highly promising for obtaining a slow drug release systemupon injection to the host body.

According to one embodiment herein, the slow release and the controlledrelease of the dexamethasone is tested in vitro. A 3 ml of thenanocarrier dispersion is poured to a dialysis sac with an atomic massof 12 KDa. The dialysis sac is placed in 50 ml phosphate buffer saline(PBS) which is stirred gently at 20 rpm at 37° C. At time 0 and thepredetermined time points a 1 ml aliquot sample is removed from theexternal medium and is replaced with fresh PBS. The drug concentrationin the aliquot sample is determined with reference to a blank free drugsolution placed at the same condition. The test reveals the slow andcontrolled release of dexamethasone from the nanocarrier ornanoparticle.

According to one embodiment herein, the dexamethasone nanocarrier ornanoparticles have many advantages i.e. in the preparation of thenanocarriers popularly available raw materials are used. Also acost-effective and simple method is used for the preparation ofnanocarriers. The biosafety of all the ingredients used in this processis well-accepted globally, as highlighted by their approval for humanuse by United States Food and Drug Administration (USFDA). The averagesize of the nanocarriers prepared makes them, on one hand, very suitablefor avoidance of the biological capture by the body defence mechanismsand, on the other hand, provides a practically reliable space for beingloaded by an adequate amount of the drug. The uniformly monodispersedparticles provide a reproducible matrix to be loaded by the same amountsof the drug in different batches, a feature very important for theindustrial production of the nanocarriers. The narrowly distributedpositive electrical potential on the nanoparticles surfaces which offersa remarkable stability both in vitro and in vivo for the nanocarriers.The constant and slow rate of the drug release from the nanoparticles,assures a long acting drug delivery system as intended by theinvestigators. The dexamethasone nanocarrier does not burst release thedrug from the nanocarriers.

FIG. 7 illustrates a schematic structure of a nanocarrier based longacting drug delivery system for dexamethasone, according to oneembodiment herein. The nanocarrier drug delivery system fordexamethasone comprises of an aqueous solution core 701. A lipid layer702 is present around the aqueous solution. A phospholipid bilayer 703is present around the lipid layer. The phospholipid bilayer has theentrapped or embedded dexamethasone drug particles 704. The outermostlayer or coating of the dexamethasone drug nanocarrier is formed by apolymer 705. The organic solvent for dissolving the lipid andphospholipid is selected from a group consisting of a methanol, anethanol, an acetone and an isopropanol. The aqueous solution is a wateror a buffer, which forms the core. The phospholipid is selected from agroup consisting of a phosphatidylcholine, a phosphatidylethanolamine, aphosphatidylinositol. The lipid is selected from a group consisting of amonostearyl glycerol, a distearyl glycerol, a palmitic acid, a stearicacid and a glyceryl stearate. The polymer is selected from a groupconsisting of a chitosan, a polyethylene glycol, a polyvinyl alcohol.

The foregoing description of the specific embodiments will so fullyreveal the general nature of the embodiments herein that others can, byapplying current knowledge, readily modify and/or adapt for variousapplications such specific embodiments without departing from thegeneric concept, and, therefore, such adaptations and modificationsshould and are intended to be comprehended within the meaning and rangeof equivalents of the disclosed embodiments.

It is to be understood that the phraseology or terminology employedherein is for the purpose of description and not of limitation.Therefore, while the embodiments herein have been described in terms ofpreferred embodiments, those skilled in the art will recognize that theembodiments herein can be practiced with modification within the spiritand scope of the appended claims.

Although the embodiments herein are described with various specificembodiments, it will be obvious for a person skilled in the art topractice the invention with modifications. However, all suchmodifications are deemed to be within the scope of the claims.

It is also to be understood that the following claims are intended tocover all of the generic and specific features of the embodimentsdescribed herein and all the statements of the scope of the embodimentswhich as a matter of language might be said to fall there between.

What is claimed is:
 1. A method for synthesizing slow and controlled release of a dexamethasone entrapped in nanoparticle or nanocarrier, the method comprising steps of: dissolving a dexamethasone in an organic solvent to get an organic solution, wherein the dexamethasone is dissolved at a concentration of 0.1 to 10 mg/ml in the organic solvent, and wherein a concentration of the organic solvent is 0.1 to 5 mg/ml; adding a phospholipid to the organic solution to form a bilayer around the dexamethasone; adding a lipid to the organic solution to obtain an organic solution mixture, wherein the organic solution mixture comprises organic solvent with the dexamethasone, phospholipid and lipid; adding the organic solution mixture by dropwise to an aqueous solution to form a lipid core, and wherein the aqueous solution is a water or a buffer, and wherein pH of the aqueous solution is in a range of 3-11, and wherein a volume ratio of the organic solution mixture to the aqueous solution is within 0.05 to 3; and adding a buffered solution of a polymer to the aqueous solution with lipid core to form a coating layer around the lipid core to obtain a nano carrier, and wherein pH of the polymer solution is in a range of 3.5 to 11, and wherein the polymer solution is added dropwise to the aqueous solution in a volume ratio of 0.05 to
 1. 2. The method according to claim 1, wherein the organic solvent is selected from a group consisting of a methanol, an ethanol, an acetone and an isopropanol.
 3. The method according to claim 1, wherein the phospholipid is selected from a group consisting of a phosphatidylcholine, a phosphatidylethanolamine, a phosphatidylinositol.
 4. The method according to claim 1, wherein the lipid is selected from a group consisting of a monostearyl glycerol, a distearyl glycerol, a palmitic acid, a stearic acid and a glyceryl stearate.
 5. The method according to claim 1, wherein the polymer is selected from a group consisting of a chitosan, a polyethylene glycol, a polyvinyl alcohol.
 6. A system for slow and controlled release of a dexamethasone entrapped in nanoparticle or nanocarrier comprises: a core of aqueous phase or solution and wherein the aqueous solution is made of water or a buffer; a lipid layer; phospholipid bilayer with the dexamethasone; and a polymer coating.
 7. The system according to claim 6, wherein the phospholipid is selected from a group consisting of a phosphatidylcholine, a phosphatidylethanolamine, a phosphatidylinositol.
 8. The system according to claim 6, wherein the lipid is selected from a group consisting of a monostearyl glycerol, a distearyl glycerol, a palmitic acid, a stearic acid and a glyceryl stearate.
 9. The system according to claim 6, wherein the polymer is selected from a group consisting of a chitosan, a polyethylene glycol, a polyvinyl alcohol.
 10. The system according to claim 6, wherein dexamethasone is water-insoluble and presents in a phospholipid bilayer during a formation of a nanovesicle, and wherein the dexamethasone gets loaded to the nanocarriers in a dissolved within a thickness of the bilayers.
 11. The system according to claim 6, wherein dexamethasone nanocarrier or nanoparticle particle size distribution curve exhibit a peak of 128.5 nm, and wherein dexamethasone nanocarrier has a relative low polydisparity index of 0.180.
 12. The system according to claim 6, wherein a dexamethasone nanocarrier or nanoparticle has a zeta potential within a range of 10 mv to 30 mv.
 13. The system according to claim 6, wherein a dexamethasone nanocarrier or nanoparticle has a zeta deviation of 4.71 mv.
 14. The system according to claim 6 wherein the dexamethasone nanocarriers or nanoparticles are administered intravenously, intramuscularly, sub-cutaneously, intra-dermally, intra-arterially, intra-thecaly and intra-cardiac routes. 